FIELD OF THE INVENTION
The present invention generally relates to novel pharmaceutical compositions or formulations containing a salt of oxaprozin for oral or other use, and to methods of treatment employing these formulations. These formulations contain only minor quantities of metallic stearates, such as the lubricants magnesium, calcium or zinc stearate, and only minor quantities of the binder methylcellulose. These formulations dissolve more rapidly, and result in a more rapid onset of the active oxaprozin salt agent than pharmaceutical formulations containing oxaprozin. Thus, these formulations are useful for the treatment of pain (as analgesic agents), as well as for the treatment of inflammation. More particularly, the present invention concerns pharmaceutical formulations containing potassium, sodium or Tris salts of oxaprozin in combination with a pharmaceutically-acceptable carrier, and methods of treating pain and inflammation employing these formulations.
Oxaprozin is a nonsteroidal antiinflammatory drug (NSAID) of the propionic acid class, chemically designated as 4,5-diphenyl-2-oxazolepropionic acid, which is currently being marketed in the United States by the pharmaceutical company G. D. Searle & Co., Skokie, Ill., under the trademark name DAYPRO.RTM.. The chemical formula for oxaprozin is: ##STR1##
DAYPRO.RTM. tablets (oral caplets) contain 600 mg of oxaprozin as the active agent and have the following formulation:
______________________________________ Ingredients Mg/Tablet % Composition ______________________________________ Oxaprozin 600.0 mg 68.37% Microcrystalline Cellulose 71.0 mg 8.09% PH-101, NF Corn Starch, NF 17.5 mg 1.99% Methylcellulose A15LVP, USP 26.3 mg 3.00% Water, mg/Tab, %*Solids 291.2 mg 0% (Lost during drying) Polacrilin Potassium 26.3 mg 3.00% IRP-88, NF Microcrystalline Cellulose 126.0 mg 14.36% PH-102, NF Magnesium Stearate, NF 10.5 mg 1.20% Total 877.6 mg 100.00% ______________________________________
In cases where a quick onset of action is important, the pharmacokinetics of oxaprozin allow therapy to be started with a one-time loading dose of 1200 to 1800 mg (not to exceed 26 mg/kg).
The potassium salt of oxaprozin has a solubility of 370 mg/ml, the TRIS salt of oxaprozin has a solubility of 380 mg/ml, and the sodium salt of oxaprozin has a solubility of 260 mg/ml compared to 1.7 mg/ml of oxaprozin. Thus, these salts of oxaprozin enable a faster dissolution and rate of absorption, leading to a more rapid onset of action and improved acute analgesic effects.
It was originally thought that the same formulation for oxaprozin which is currently marketed in the United States by G. D. Searle & Co. under the trademark name DAYPRO.RTM. could be employed for a potassium, sodium or Tris salt form of oxaprozin. However, it was discovered that tablets made from such formulation for the potassium salt of oxaprozin were deformed and would not disintegrate in water or dissolve in phosphate buffer media, with the result that little or no active agent was being released from these tablets during the first hour.
It is believed that the magnesium in the magnesium stearate (employed as a lubricant in the DAYPRO.RTM. formulation) was interacting with the potassium in tablets containing the potassium salt of oxaprozin and thereby forming a complex which produced an insoluble gel which prevented the tablets from disintegrating and dissolving.
It was subsequently determined that the magnesium stearate employed in the potassium, sodium and Tris oxaprozin salt formulations was not the only ingredient of these formulations which was adversely affecting the disintegration and dissolution of tablets containing these formulations. It is now theorized that disintegration and dissolution of these tablets was adversely affected by both the lubricant magnesium stearate and the binder methylcellulose.
It is desirable to develop pharmaceutical formulations of the present invention wherein about 75% of the active ingredient (potassium, sodium or TRIS salt of oxaprozin) becomes dissolved in phosphate buffer media within about 30 minutes. The most preferred pharmaceutical formulation has the characteristic that about 100% of the potassium salt of oxaprozin becomes dissolved in phosphate buffer media within 30 minutes. In comparison, when the potassium salt of oxaprozin was originally substituted for oxaprozin in the current DAYPRO.RTM. formulation, only about 23% of the potassium salt of oxaprozin became dissolved in phosphate buffer media within 30 minutes.
Because tablet formulations containing the potassium salt of oxaprozin dissolve more rapidly and the potassium salt of oxaprozin has a significantly higher solubility than oxaprozin, the tablet formulations containing the potassium salt of oxaprozin have a significantly more rapid onset of action of the active agent in comparison with DAYPRO.RTM.. As a result, tablet formulations containing a potassium salt of oxaprozin are useful as analgesic agents for the treatment of pain, as well as anti-inflammatory agents for the treatment of diseases such as rheumatoid arthritis and osteoarthritis.